JP2009508959A - Rosiglitazone and donepezil combination for improved cognitive function - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising, among others, rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt therapy thereof for use in the treatment or prevention of Alzheimer's disease or other dementia and mild cognitive impairment . The present invention also relates to an oral dosage form comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof.

Description

  The present invention relates to, inter alia, compositions, their use in the treatment or prevention of mild cognitive impairment, Alzheimer's disease or other dementias and therapies or prophylaxis using the compositions. In particular, the invention relates to a composition comprising a cholinesterase inhibitor, in particular donepezil, together with a PPARγ agonist, in particular rosiglitazone.

  Alzheimer's disease (AD) was first described in 1907 by the Bavarian Alois Alzheimer. It is a progressive, debilitating disease and the most common cause of dementia. Typical symptoms include memory impairment, cognitive impairment, behavioral changes (including paranoia, delusions, loss of suppression) and decreased language function. Pathologically, AD is traditionally characterized by the presence of two different brain disorders-the neuritic plaque (sometimes referred to as the senior plaque) and neurofibrillary tangles. Yes.

  Senile plaques are extracellular amyloid β-protein (Aβ) deposits, typically about 10-150 μm in cross-section in the striatum, associated with axon and dendritic damage. Aβ is formed by cleavage of amyloid precursor protein (APP) by a series of secretases. The 40-residue peptide, Aβ40, is the form of Aβ that is normally produced by cells in the largest amount, but many Aβ found in the senile population contain 42 amino acids (Aβ42). Although Aβ40 is also localized in the plaque, Aβ42 is significantly more hydrophobic than Aβ40 and therefore tends to aggregate more. The elderly group is thought to develop over a sufficient period (months to years). Although the correlation between the extent of amyloid deposition and cognitive impairment is an issue, amyloid deposition in the form of plaque is known to occur before the appearance of clinical symptoms.

  Neurofibrillary tangles are usually found in perinuclear cytoplasmic neurons from AD patients. The change is formed from a pair of fibers with wounds in the helix. These extremely insoluble fibers are known to consist of abnormally hyperphosphorylated microtubule-associated protein tau. There is some evidence that the formation of changes is a neuronal response to the gradual accumulation of Aβ.

  Although clinically typical AD can be autosomal dominant, most cases of disease (about 90%) are considered sporadic. Except that more rare familial AD is generally present much earlier than sporadic AD (eg, often also known as late-onset AD or LOAD), these two forms of disease are expressed The similarity is very high on the mold. This general phenotypic similarity suggests that the information that characterizes the autosomal dominant types (such as APP mutations and presenilin 1 and 2 genes) is associated with late sporadic AD. In general, familial AD is associated with increased production of Aβ, while sporadic AD may be the result of failure of clearance of regular Aβ production.

  A number of influential factors have been identified for sporadic AD, including age, low cholesterol concentration, high maximal blood pressure, high glucose concentration, high insulin concentration, impaired glucose tolerance and the presence of the e4 allele of apolipoprotein E ( Kuusisto J et al. BMJ 1997 315: 1045-1049).

  For more information on AD, see generally Selkoe D Physiol. Rev. 2001 81 (2): 741-766; Watson G et al. See CNS Drugs 2003 17 (1): 27-45.

  Mild cognitive impairment is a condition in which a subject has a slight impairment of cognitive function that can be detected from the baseline date before onset, but is not too severe to meet the diagnostic criteria for AD. As such, MCI can be considered as a transition state between the normal cognitive function of a normal aging subject and the abnormal cognitive function of dementia. MCI can be categorized based on the type of cognitive impairment detected. Loss of memory simply represents a characteristic of amnestic MCI; whereas other types of MCI relate to the loss of multiple recognition regions, including memory, or the loss of a single, non-memory region. The rate of progression from amnestic MCI to AD has been measured in a cohort study ranging from 10-20% per year (see Petersen et al. Arch Neurol 2001 58: 1985-1992 for more information).

  Similarly, other dementias that cause cognitive impairment include vascular dementia, Lewy body dementia, frontotemporal dementia and dementia associated with Parkinson's disease.

  Apolipoproteins are glycoproteins associated with brain development, synaptogenesis and response to neuronal damage. Apolipoprotein E (ApoE) is one protein component of plasma lipoprotein. There are three major isoforms of ApoE (ie, ApoE2, ApoE3 and ApoE4) that are the products of three alleles at a single locus. Thus, the individual may be homozygous (APOE2 / 2, APOE3 / 3 or APOE4 / 4) or heterozygous (APOE2 / 3, APOE2 / 4 or APOE3 / 4). The most common allele is APOE3 (Bales KR et al. Mol. Interventions 2002 2: 363-375), with the allele frequency of ca. 0.78 in the Caucasian population, and the most common genotype is APOE3. / 3.

The amino acid sequences of the three isoforms show only minor changes and are summarized in Table 1 below.

  The association between APOE4 allele transport and the risk of developing AD has been previously known and well documented (Strittmatter WJ et al. PNAS 1993 90: 1977-1981; Roses AD Ann). Rev Med 1996 47: 387-400). However, the presence of the e4 allele is a susceptibility factor and does not cause disease, so APOE genotype alone is not a sufficient diagnostic test for AD (Mayeux R et al. New Engl. J. Med. 1998 338: 506 -511).

  It has been shown that age-adjusted risk of AD in individuals with two APOE4 alleles is more than three times that of individuals with only one APOE4 allele, and then nearly that of individuals without the APOE4 allele 3 times (Corder et al. Science 1993 261 (5123): 921-3; Kuusisto J et al. BMJ 1994 309: 636-638). Compared to other AD patients, individuals who are homozygous for APOE4 show an aging onset, increased amyloid levels and decreased acetylcholine levels. We found that APOE4 allele frequency varies from ethnic population to about 0.15 in Caucasian populations but up to 0.4 in patients with AD (Saunders et al. Neurology 1993 43 (8). : 1467-72).

  APOE2, which is the rarest of the three common alleles, indicates that it has a protective effect compared to the most common APOE3 allele, individuals with the APOE2 allele are generally more diseased than individuals without the APOE2 allele (Corder et al. Nature Genetics 1994 7 (2): 180-4; Bales KR et al. Mol Interventions 2002 2: 363-375). The APOE2 allele frequency was found to be about 0.07 in the Caucasian population. There is more recent data that once APOE4 status is not related to the rate of progression once possible AD symptoms exist.

  Glucose metabolism is very important in the function of cells in the central nervous system. A decrease in cerebral glucose metabolism that is region-specific has been demonstrated in patients with AD (Reiman EM et al. New Eng J Med 1996 334: 752-758; Alexander, GE et al. Am J Psychiatry 2002 159: 738-745). , Both in LOAD and in family AD (Small GW et al., PNAS 2000 97: 6037-6042).

  Patients at risk for AD because reduced cerebral glucose metabolism in a region-specific pattern can be found many years prior to the predicted age of onset of clinical symptoms in individuals carrying one or two APOE4 alleles The decrease in cerebral glucose metabolism in is associated with APOE status (Reiman EM et al. New Eng J Med 1996 334: 752-758; Rossor M et al, Anals NY Acad Sci 1996 772: 49-56; Small GW et al., PNAS 2000 97: 6037-6042).

  Insulin is also very important for peripheral and central energy metabolism. Secreted by the pancreatic β-cells, plasma insulin serves to regulate the blood glucose concentration, the rate of glucose uptake of insulin-sensitive tissue controlled by the insulin-sensitive glucose transporter, through the timing of feeding and fasting. An increase in blood glucose results in the release of insulin, while a decrease in blood glucose results in the release of counter-regulatory hormones that increase the glucose produced by the liver. Type II diabetes results from decreased insulin capacity that stimulates glucose uptake and inhibits hepatic glucose production (known as insulin resistance) as well as insufficient insulin secretion response to compensate for insulin resistance.

  Insulin permeates the blood / brain barrier by an insulin receptor-mediated transport method. Peripheral concentrations of insulin tend to coincide with concentrations in the central nervous system (CNS), ie increased peripheral insulin results in increased CNS insulin. It suggests that insulin is involved in normal memory function and that disorders in peripheral insulin metabolism such as insulin resistance and hyperinsulinemia can adversely affect memory. Increased insulin-stimulated glucose utilization can lead to glycolytic production of acetyl CoA, a major substrate in the synthesis of the neurotransmitter acetylcholine. A decrease in acetylcholine concentration is a major feature of AD.

  Peroxisome proliferator-activated receptor γ (PPAR-γ) is an orphan group of the ligand-activated transcription factor steroid / thyroid / retinoid receptor superfamily. PPAR-γ is one of a closely related subfamily of PPARs encoded by independent genes (Dreyer C et al. Cell 1992 68: 879-887; Schmidt A et al. Mol. Endocrinol. 1992 6: 1634- 1641; Zhu et al. J. Biol. Chem. 1993 268: 26817-26820; Kliewer SA et al. Proc. Nat. Acad. Sci. USA 1994 91: 7355-7359). Three mammalian PPARs have been isolated and designated as PPAR-α, PPAR-γ and PPAR-δ (also known as NUC-1). These PPARs regulate the expression of target genes by binding to DNA sequence elements called PPAR response elements (PPRE). To date, PPRE encodes a protein that regulates lipid metabolism and has been identified as an enhancer of a number of genes that indicate that PPAR plays a pivotal role in the adipogenic signaling cascade and lipid homeostasis (Keller) H et al. Trends Endocrin. Met. 1993 4: 291-296).

  European Patent No. 306228 describes a group of PPAR-γ agonists that are thiazolidinedione derivatives for use as insulin sensitizers in the treatment of type II diabetes. These compounds have antihyperglycemic activity. One preferred compound described herein is known as the chemical name 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione. The common name rosiglitazone has been given. Salts of the compounds, including maleate, are described in WO 94/05659. European patent applications, publication numbers: 0008203, 0139421, 0032128, 0428312, 04886363, 0155845, 0257781, 0208420, 0177353, 0319189, 0323331, 0333332, 0528734, 0508740; International patent applications, publication numbers: 92/18501, 93/02079, 93/22445 and US Pat. Nos. 5,104,888 and 5,478,852 also disclose certain thiazolidinedione PPAR-γ agonists. 5- [4- [2- (5-Ethyl-2-pyridyl) ethoxy] benzyl] thiazolidine-2,4-dione (also known as pioglitazone), 5- [4-[(1-methylcyclohexyl) methoxy] benzyl ] Thiazolidine-2,4-dione (also known as ciglitazone), 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran- 2-yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (also known as troglitazone) and 5-[(2-benzyl-2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidine-2,4 -Specific compounds may be mentioned, including diones (also known as englitazone).

  US Pat. No. 6,294,580 (the disclosure of which is hereby incorporated by reference) is not a thiazolidinedione compound but instead is also effective as an insulin sensitizer in the treatment of type II diabetes A series of PPARγ agonists are described which are O- and N-substituted derivatives of tyrosine. One such compound has the chemical name N- (2-benzoylphenyl) -O- [2- (5-methyl-2-phenyl-4-oxazolyl) ethyl] -L-tyrosine (2 (S)-(2- Benzoylphenylamino) -3- {4- [2-5-methyl-2-phenyl-oxazol-4-yl) -ethoxy] -phenyl} -propionic acid, or commonly known as farglitazar).

  Numerous clinical evidences suggest that disturbances in cerebral glucose metabolism are present in APOE4 carriers during AD and before the clinical onset of AD symptoms (Reiman EM et al. New Eng J Med 1996 334: 752-758; Rossor M et al., Annals NY Acad Sci 1996 772: 49-56; Small GW et al., PNAS 2000 97: 6037-6042).

  Clinical and epidemiological evidence that converges that the risk of developing AD can affect insulin resistance also suggests. However, the exact nature of the relationship between insulin resistance and AD is complex and has not been well understood.

  Hyperinsulinemia is known as a risk factor for AD. In one study, it was concluded by the authors to be APOE genotype independent (Kusisto J et al. BMJ 1997 315: 1045-1049), where hyperinsulinemia without the APOE4 allele (APOE4-) Elderly subjects with diabetes have an AD prevalence of 7.5% in hyperinsulinemia subjects compared to 1.4% in normoinsulinemia subjects; whereas the APOE4 allele ( A hyperinsulinemia elderly subject with APOE4 +) had 7.0% AD prevalence in hyperinsulinemia subjects compared to 7.1% in normoinsulinemia subjects . Other studies have shown a causal relationship between APOE genotype and insulin resistance (Watson G et al. CNS Drugs 2003 17 (1): 27-45).

  For example, patients who were not homozygous for the APOE4 allele have abnormalities in insulin metabolism (especially increased plasma insulin concentrations), indicating possible factors in the development of AD in these patients, whereas APOE4 Patients who were homozygous for the allele demonstrated normal peripheral concentrations of insulin. Both groups demonstrated reduced cerebrospinal fluid insulin concentrations compared to non-AD subjects (Craft S et al. Neurology 1998 50: 164-168). In addition, patients without the APOE4 allele had a reduced rate of insulin-mediated glucose treatment compared to patients who were APOE4 + (Craft S et al. Neuroendocrinology 1999 70: 146-152).

  It is well recognized that the proper functioning of mental functions such as memory is necessary. Numerous evidences indicate that AD patients have cholinergic signaling abnormalities, the extent of which correlates with the concentration of cognitive impairment. As with many aspects of AD research, the causal relationship between disease progression and observed cholinergic dysfunction is not fully understood. Numerous cholinesterase inhibitors have so far demonstrated muscarinic or nicotinic acetylcholine receptors, despite demonstrating sufficient efficacy with acceptable acceptable side effects for use in the treatment of AD. The use of agonists for GI has not proven to be of clinical value, these include tacrine (Cognex®), galantamine (Reminyl / Radazyne®), rivastigmine (Exelon®) )) And donepezil (Alicept®). For further details see, for example, Terry AV et al. J. et al. Pharmacol. Exp. Ther. 2003 306 (3): 821-827.

  In a recently published study investigating the use of donepezil in individuals with mild cognitive impairment (normal aging and early AD transition state), although there was no distinction between groups at 3 years, donepezil was During the first 12 months patients showed a reduced rate of developing AD. In addition, a significant effect was seen in the first 12 months, followed by a more rapid decline in the next 24 months. Patients who were carriers of one or two copies of the APOE4 allele were at risk of progressing to AD compared to placebo, although no significant difference in overall objectives of treating the population compared to placebo was observed for 3 years Sex was decreased (Petersen R et al. New Engl. J. Med. 2005 352: 2379-2387).

  The use of insulin sensitizers in the treatment of AD has already been proposed. International patent application WO 98/39967 discloses a method of treating or preventing AD by administering an agent that reduces serum insulin levels, such as thiazolidinedione. International Patent Application WO 99/25346 describes a method for treating or preventing diseases mediated by apoptosis, such as neurodegenerative disorders including AD and Parkinson's disease, by administering an apoptosis inhibitor, for example, an insulin sensitizer such as rosiglitazone. Is disclosed. International patent application WO 00/32190 discloses a method for treating or preventing AD by administering PPAR-γ agonists such as thiazolidinedione derivatives pioglitazone and rosiglitazone. International patent application WO 00/35437 discloses a method for improving mental behavior in a subject suffering from reduced mental behavior by administration of insulin sensitizers such as the thiazolidinedione derivatives pioglitazone and rosiglitazone.

  In Parkinson's disease models, thiazolidinedione derivatives (including rosiglitazone and pioglitazone) are acetaldehyde (Jun et al. (2006) Biochem Biophys Res Comm 340, 221-227), MPTP (Dehmer et al. (2004) J Neurochem 88,494-501. ) And 8-OHDA (Chen et al. (2004) FASEB 18,1162-1164) have been shown to protect dopaminergic cells from a variety of toxic injuries.

  Although both PPAR-γ agonists such as rosiglitazone and cholinesterase inhibitors such as donepezil have been shown to be used in the treatment of mild cognitive impairment and AD, it is shown in any prior art that they can be used in combination. It has not been.

  Accordingly, in a first aspect of the present invention there is provided a composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or alone. .

  It is substantially included that the pharmaceutically acceptable diluent or carrier may be a mixture of substances, ie, a combination of one or more pharmaceutically acceptable diluents or carriers.

  WO 03/061648 relates to the use of acetylcholinesterase inhibitors such as donepezil for reducing insulin resistance and for treating type II diabetes. Other drugs used to treat diabetes may be combined with acetylcholinesterase inhibitors, including insulin and insulin analogs; sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinones The literature teaches that the system, and type II diabetes drugs such as the meglitinide system; phosphodiesterase inhibitors; cholinergic agents; nitric oxide donors; antioxidants; Although rosiglitazone is one of the drugs identified in the long list, a combination of rosiglitazone and an acetylcholinesterase inhibitor would be preferred over a combination with one of the many other drugs on the list provided There is no suggestion to do. There are no examples of combining acetylcholinesterase inhibitors with other drugs.

  WO 2005/074917 relates to conditions associated with diabetes such as diabetes or cognitive impairment using phenserine-like compounds such as donepezil, galantamine or tacrine. The document teaches that phenserine-like compounds may be used in combination with hypoglycemic agents such as sulfonylureas, meglitinides, biguanides, thiazolidinediones or α-glucosidase inhibitors. Again, there is no example of a phenserine-like compound in combination with another drug, and there is no suggestion that rosiglitazone will be used over any of the other hypoglycemic agents shown .

  In contrast to the prior art, the compositions of the present invention are intended to improve cognitive function in subjects suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia, not the treatment of diabetes. Yes.

  Accordingly, the present invention relates to rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a thereof for use in improving cognitive function in a subject suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia Compositions comprising a pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier are provided.

  Further, a method of improving cognitive function in a subject suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia, rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable thereof There is provided a method comprising administering to a subject a safe and effective amount of a composition comprising salt.

  In yet another aspect, the invention provides rosiglitazone or a pharmaceutically acceptable thereof in the preparation of a medicament for improving cognitive function in a subject suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia Further provided is the use of a composition comprising a salt prepared and donepezil or a pharmaceutically acceptable salt thereof.

  A further aspect of the invention is rosiglitazone or a pharmaceutically acceptable thereof for simultaneous, separate or sequential use in improving cognitive function in subjects suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia A combination of a salt and donepezil or a pharmaceutically acceptable salt thereof is provided. A related aspect is a method for improving cognitive function in a subject suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia, and in combination, rosiglitazone or a medicament thereof for simultaneous, separate or sequential use There is provided a method comprising administering to the subject a top acceptable salt and donepezil or a pharmaceutically acceptable salt thereof. A related aspect is rosiglitazone or a combination thereof in the manufacture of a medicament for simultaneous, separate or sequential use in combination to improve cognitive function in subjects suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia Provided are pharmaceutically acceptable salts and use of donepezil or a pharmaceutically acceptable salt thereof.

  Contradicts with reports on the effect of the APOE4 allele in the treatment of mild cognitive impairment, Alzheimer's disease or other dementia with cholinesterase inhibitors. When treating patients with AD with tacrine, 83% of non-APOE4 holders showed improved cognitive function, whereas 60% of APOE4 holders had no change or worsened after 30 weeks. Poirier et al. (Proc. Natl. Acad. Sci. USA (1995), 92, 12260-12264) teaches.

  However, they cannot confirm the relationship between the POE4 allele and no response to donepezil therapy, Greenberg et al. (Arch. Neurol., (2000), 57, 94-99) state that the APOE genotype is donepezil. Winblad et al. (Neurology (2001), 57, 489-495) teaches that it does not affect a significant response to treatment.

  Prior to the earliest priority date of the present application, the use of a PPARγ agonist such as rosiglitazone to improve cognitive function in subjects suffering from or susceptible to MCI, AD or other dementia was homozygous for the APOE4 allele. There was no clear basis for providing benefits only to non-type subjects and most benefiting subjects who are non-carriers of the APOE4 allele.

  However, we now note that the PPARγ agonist rosiglitazone is significantly more effective in treating patients who are not homozygous for the APOE4 gene and is most effective in treating patients who do not carry the APOE4 allele. Showed.

  Thus, the compositions of the present invention may provide the greatest benefit to patients who are not homozygous for APOE4, and in embodiments of the invention described above, the subject is pre- Preferably, it has been determined. The target may be determined in advance to be APOE4-, for example.

According to another aspect of the invention, a method for improving cognitive function in a subject suffering from or susceptible to MCI, Alzheimer's disease or other dementia, wherein the subject is not homozygous for the APOE4 allele. ,Less than:
i) screening the subject to determine that the subject is not homozygous for the APOE4 allele; then ii) a safety comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof And a method comprising administering to the subject an effective amount of the composition.

  Screening method (i) may be involved in determining whether a subject has an APOE2 or APOE3 allele.

  In one embodiment of the invention, screening step (i) relates to determining that the subject carries a single copy of the APOE4 allele. For example, the subject may be determined to be APOE3 / APOE4.

  In a more preferred embodiment of the invention, the screening step (i) relates to determining that the subject is APOE4- (ie does not carry the APOE4 allele). For example, the subject may be determined to be APOE3 / APOE3 or APOE2 / APOE3.

  For example, the subject may be suffering from or susceptible to MCI or AD (eg, may be suffering). In one embodiment of the invention, the subject is suffering from MCI (particularly amnestic MCI). In another embodiment of the invention, the subject is suffering from Alzheimer's disease. In another embodiment of the invention, the subject is susceptible to MCI (particularly amnestic MCI). In another embodiment of the invention, the subject is susceptible to Alzheimer's disease. In further embodiments, the subject is suffering from or susceptible to other dementias, such as vascular dementia, Lewy body dementia, frontotemporal dementia or dementia associated with Parkinson's disease.

  For administration of a composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof, comprising screening to determine whether the subject carries 0 or 1 copy of the APOE4 allele Also provided in accordance with the present invention is a method of screening a subject suffering from or susceptible to MCI, Alzheimer's disease or other dementia as an aid in predicting a subject's response.

  The method may particularly comprise a screening to determine whether the subject is APOE4-.

  (I) rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof to a subject that is not homozygous to the APOE4 allele (for example, a subject that has been previously determined not to be homozygous to the APOE4 allele) Also provided is a kit comprising a composition comprising an acceptable salt (ii) instructions for use in administering a PPARγ agonist (typically in the form of a pharmaceutical composition). For example, the instructions direct administration of the composition to a subject suffering from or susceptible to MCI, Alzheimer's disease or other dementia that is not homozygous for the APOE4 allele. According to a particular aspect of the invention, the subject is APOE4- (eg, the subject is predetermined to not have any copy of the APOE4 allele).

  The kit may optionally include one or more reagents that determine whether the subject has 0, 1 or 2 APOE4 alleles. Such a reagent may typically be selected from the group consisting of probes, primers, antibodies and combinations thereof.

  Alternatively, in the above aspects of the invention, the subject may carry a single copy of the APOE4 allele, or may be determined or predetermined to be retained. For example, the subject may be determined to be APOE3 / APOE4 or predetermined.

  As demonstrated in the examples below, the inventors have shown that the PPARγ agonist rosiglitazone has a clinically cognitive function compared to placebo in subjects with mild to moderate AD who do not carry the APOE4 allele. Surprisingly found to bring relevant improvements. The results suggest that patients carrying one copy of the APOE4 allele experience stabilization of cognitive impairment (ie, neither significant improvement nor reduction) in treatment with rosiglitazone.

  Although it is not clear whether the decline is due to treatment outcome or the natural progression of the disease, patients who are homozygous for the APOE4 allele may experience clinical decline with treatment with rosiglitazone The results suggest.

  Without being limited by theory, the inventors have sought to streamline the present invention. According to one theory, amino acid sequence differences between isoforms result in differences in their protein folding. In particular, ApoE2 and ApoE3 are characterized by the presence of Cys at position 112 and Arg at position 61. ApoE4 is characterized by the presence of Arg at position 112 and Arg at position 61. Residues 61 and 112 interact in the folded protein, Arg is positively charged and Cys is negatively charged, so the ApoE2 and ApoE3 protein folds are closer in the region than the ApoE4 protein folds. Although ApoE isoforms undergo intracellular degradation, as a result of the conformational differences between isoforms, ApoE4 is believed to experience a high rate of degradation. Fragments resulting from degradation have lipid and receptor binding sites that simultaneously cause mitochondrial toxicity. The lipid binding site of the ApoE4 fragment appears to be a stronger lipid binder than the site of ApoE2 or ApoE3 fragment. Thus, ApoE4 fragments bind to a greater extent than ApoE2 and ApoE3 fragments and cause mitochondrial division; the division also affects mitochondrial transport of synapses from somatic cells. The division may also indicate a decrease in mitochondrial responsiveness to an increase in glucose or lactate base resulting from treatment with a PPARγ agonist. The effect would be expected to be better for subjects with 2 copies of the APOE4 allele than those with 1 copy and better for subjects with 1 copy of the APOE4 allele than those without copies.

  A pre-determination of whether a subject carries 0, 1 or 2 copies of APOE4 allele may be made by the APOE4 screening method described herein.

  In one embodiment of the invention, the subject will suffer from type II diabetes. In another embodiment of the invention, the subject will not suffer from type II diabetes.

  The preparation of subject diagnostic screening to determine the presence or absence of the APOE4 allele is well documented and within the ability of one skilled in the art.

  The deletion of the APOE4 allele indicates the presence of the APOE2 and APOE3 alleles either directly or indirectly, eg, by a negative result in a test indicating the presence of the allele (so that the APOE4 allele is present) It may be determined by the positive result of the test (excluding the possibility).

  The screening method may be based on a number of techniques such as isoelectric focusing, immunological methods, immunochemical methods or sequencing methods (either the ApoE protein itself or the nucleic acid encoding it). Particular methods include PCR-based methods using restriction fragment enzymes or TaqMan primers.

  The immunological method relates to the detection of ApoE isoforms by the use of isoform specific antibodies. However, immunological detection methods can be hampered by problems with antibody cross-reactivity that can affect the reliability of the results.

  Immunochemical methods include those described in International Patent Application WO 94/09155 (related to granted patents EP0625212, JP03265777 and US5508167) and disclose a method for detecting the presence or absence of ApoE4 for the diagnosis of AD. The method for detecting the presence or absence of ApoE4 disclosed in WO94 / 09155 is also used in the practice of the present invention. Briefly, a sample from a subject (eg, a blood sample) is contacted with a solid support that is specifically designed to react with sulfhydryl groups. The liquid sample is then separated from the solid support and tested for the presence of ApoE by use of an appropriate support. The presence of ApoE4 in the isolated sample indicates that the subject is a carrier of the APOE4 allele. Unlike ApoE2 and ApoE3, ApoE4 protein does not contain any cysteine residues and therefore does not react and immobilize on a solid support. The presence of unbound ApoE in the liquid sample after passing the solid support that the individual is ApoE4 + is indicated; the absence of ApoE immunoactivity in the liquid sample after passing the solid support that the individual is ApoE4- Show. Since it does not require immunological differentiation of the ApoE isoform, the problem of antibody specificity is largely denied by the technique.

  The sequence approach involves the isolation and purification of either ApoE protein or ApoE-encoding DNA from a subject, determination of amino acid or DNA sequences by general techniques, and known amino acid or DNA sequences for alleles that differ from the results. Regarding comparison.

  A preferred method for determining APOE genotype is PCR-based methods—using primary PCR of some APOE genes, followed by digestion with restriction enzymes that recognize DNA substitutions that identify alleles and gel electrophoresis, or most commonly Relates to the use of TaqMan real-time PCR. In particular, APOE genotyping can be performed using an established Taqman protocol, a fluorescence detection system that relies on a 5'-nuclease assay with an allele-specific fluorescent probe. When the probes bind to the template, only these probes fluoresce. The method is described in Macleod et al. Eur J Clinical Investigation 2001 31 (7): 570-3. Commercial products for determining the APOE genotype are available from Lab Corp and Athena Diagnostics.

  Improvement in cognitive function in a patient can be determined by one or more established methods, such as ADAS-cog and / or CIBIC + and / or DAD methods, each of which is described elsewhere in this specification. And related documents are hereby incorporated by reference in their entirety). A preferred method is ADAS-cog. Suitably, the improvement in ADAS-cog is at least 1 point, especially at least 2 points over a 24 week treatment period.

  Another possible method is the Buschke Selective Reminding Test (Grober E et al. Neurology 1988 38: 900-903).

  “Improved cognitive function” represents an improvement in cognitive treatment by medication over time compared to an individual who has not received treatment. Because patients with dementia (eg, AD) typically have a decline in cognitive function over time, “improving cognitive function” includes delaying or preventing decline as well as complete improvement. As shown in Example 2, it appears that the complete improvement in cognitive function stems from the preferred method of practicing the present invention.

  It will be apparent to those skilled in the art that rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof can be present in the form of a pharmaceutically acceptable solvate.

  Suitable solvates include hydrates.

  Suitable pharmaceutically acceptable salts of rosiglitazone and donepezil include those formed with organic and inorganic acids or bases.

  Pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid. Acid, oxalic acid, fumaric acid, maleic acid, malic acid, glutamic acid, aspartic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, arylsulfonic acid (for example, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid or Naphthalenedisulfonic acid), salicylic acid, glutaric acid, gluconic acid, tricarballylic acid, cinnamic acid, substituted cinnamic acids (including, for example, phenyl, methyl, methoxy or halo substituted cinnamic acids, 4-methyl and 4-methoxy cinnamic acid), Ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (eg 1- or 3-hydroxy-2-naphthoic acid), naphthalene acrylic acid (eg naphthalene-2-acrylic acid), benzoic acid, 4-methoxybenzoic acid, 2- or 4-hydroxybenzoic acid, 4-chloro Included are those formed from benzoic acid, 4-phenylbenzoic acid, benzeneacrylic acid (eg, 1,4-benzenediacrylic acid) and isethionic acid.

  Pharmaceutically acceptable salt addition salts include alkali metal salts such as ammonium, sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and dicyclohexylamine and N-methyl-D-glucamine. Salts with organic bases are included.

  Independently or in combination, it is particularly preferred that rosiglitazone is in the form of rosiglitazone maleate and donepezil is in the form of donepezil hydrochloride.

  Donepezil and its salts may also exist in multiple polymorphisms, and any of these forms may be used in the present invention.

  The most suitable route may depend, for example, on the condition of the recipient, but suitable formulations include oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation (various types Metered dose aerosol, particulate dust or mist that can be generated by nebulizer or inhaler), transdermal (eg, via a skin patch), rectal and topical (including skin, oral, sublingual and intraocular) administration Things are included. The formulations are conveniently present in unit dosage form and can be prepared by any of the methods known in the pharmaceutical arts. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are uniformly and intimately prepared by associating the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

  Formulations used in the present invention suitable for oral administration are as discrete units such as capsules, capsules or tablets each containing a predetermined amount of the active ingredient; as powders or granules; aqueous or non-aqueous liquids It may be present as a solution or suspension; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be present as a bolus, electuary or paste.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared by compressing in a suitable machine the free-flowing form of the active ingredient, such as powders or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. sell. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound soaked with an inert liquid diluent. Tablets may be coated or divided as desired, and may be formulated to provide sustained or controlled release or sustained release active ingredients therein.

  Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats and solutes that make the formulation isotonic with the blood of the intended recipient, and suspensions Aqueous and non-aqueous sterile suspensions that may contain agents and thickeners are included. Formulations may be present in single or multi-dose containers, such as sealed ampoules and vials, which are freeze-dried (frozen) that require only the addition of a sterile liquid carrier, such as saline or water for injection, just prior to use. (Dry) conditions may be stored. Necessary injection solutions and suspensions can be prepared from sterile powders, granules and tablets as described above.

  Dry powder compositions for topical delivery to the lungs by inhalation may be included in, for example, capsules and, for example, gelatin capsules or, for example, layered aluminum foil blisters, for use in inhalers or inhalers. Powder mixture formulations generally comprise a powder mixture for inhalation of a compound of the invention and a suitable powder base (carrier / diluent / excipient material) such as a monosaccharide, disaccharide or polysaccharide (eg lactose or starch). Containing. The use of lactose is preferred.

  Spray compositions for topical delivery to the lungs by inhalation can be formulated, for example, with the use of a suitable liquefied high pressure gas, as an aqueous solution or suspension, or as an aerosol delivered from a pressurized pack such as a metered dose inhaler. Aerosol compositions suitable for inhalation can be either suspensions or solutions, and generally include other therapeutically active ingredients and suitable high pressure gases such as fluorocarbons or hydrogen containing chlorofluorocarbons or the like. Mixtures, in particular hydrofluoroalkanes such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, in particular 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3, 3-Heptafluoro-n-propane or a mixture thereof is optionally combined to contain the compound of formula (I). Carbon dioxide or other suitable gas can also be used as the high pressure gas. The aerosol composition may be a free excipient or desired additional formulation excipients known in the art such as surfactants such as oleic acid or lectin and co-solvents such as ethanol. May be contained. The pressurized formulation will generally be held in a container (eg, an aluminum container) closed with a valve (eg, a metering valve) and will be adapted to an actuator equipped with a mouthpiece.

  Agents for administration by inhalation desirably have control particles. The optimum particle size for inhalation into the bronchial system is usually 1-10 um, preferably 2-5 um. When inhaled to reach the peripheral airways, particles having a size greater than 20 um are generally too large. In order to achieve these particle sizes, the active ingredient particles as produced may be reduced in size by conventional methods, for example by micronization. The desired fraction may be separated by air classification or sieving. Preferably the particles will be crystalline. If a diluent / excipient such as lactose is used, generally the particle size of the excipient will be significantly larger than the inhaled drug in the present invention. Where the excipient is lactose, typically up to 85% lactose particles will be present as ground lactose, which will have 60-90 um MMD and at least 15% will have less than 15 um MMD. I will.

  Intranasal sprays can be formulated in aqueous or non-aqueous vehicles with the addition of agents such as thickeners, buffer salts or acids or alkalis that adjust pH, isotonicity adjusting agents or antioxidants.

  Nebulized inhalation solutions can be formulated in aqueous vehicles with the addition of agents such as acids or alkalis, buffer salts, isotonicity adjusting agents or antibacterial agents. They can be sterilized by filtration or heating in an autoclave, or lost as a non-sterile formulation.

  Rectal administration formulations may exist as suppositories with conventional carriers such as cocoa butter or polyethylene glycol.

  Formulations for topical administration in the mouth, e.g., oral cavity or sublingual, include sucrose and a drop containing the active ingredient of a flavored ingredient such as acacia or tragacanth, and an active ingredient of the active ingredient such as glycerin and glycerin or sucrose and acacia Includes lozenges.

  In particular, in addition to the above ingredients, the formulation of the present invention may include other drugs common in the art in view of the type of formulation in question, eg suitable for oral administration. It will be appreciated that perfume additives may be included.

  The composition is preferably formulated for oral administration.

  One problem that arises when formulating compositions containing both rosiglitazone and donepezil is that the two drugs have vastly different pharmacokinetic characteristics. In order to obtain the optimal pharmacokinetic profile of rosiglitazone, the drug prescribed in the immediate release dosage form is sometimes administered to the subject twice daily. If the improved dosage form provides such as that described in WO2005 / 013935, the drug need only be administered once a day. The document teaches a formulation of rosiglitazone comprising a core containing two different active ingredients, an immediate release formulation and a modified release formulation. The tablets are surrounded by a coating, such as ethylcellulose, whose holes penetrate from one to an immediate release depot and from one to a modified release depot. The arrangement ensures a very controlled release of rosiglitazone to obtain an optimal pharmacokinetic profile.

  On the other hand, donepezil has different pharmacokinetic characteristics to rosiglitazone, and it is generally not necessary to provide a modified release formulation to achieve a once-daily dosage.

  Any oral formulation containing both rosiglitazone and donepezil is designed to ensure that an acceptable pharmacokinetic profile is achieved for both drugs, especially if a once-daily dosage form is required. This means that it will be.

  Surprisingly, the inventors believe that donepezil may produce a formulation similar to that of WO2005 / 013935 that is included in the immediate release formulation without substantially affecting the release profile of rosiglitazone. ing. Such formulations form a further aspect of the invention.

Thus, in yet another aspect of the invention,
A first composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof formulated in an immediate action form through an aqueous medium; and formulated for modified release through an aqueous medium; An oral dosage form comprising a second composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof is provided.

  The term “modified release” means a composition that is designed to produce the desired pharmacokinetic profile, and includes single or any combination of delayed pulse and sustained release formulations. Generally, however, the second composition is formulated for sustained release, optionally combined with delayed release.

  The oral dosage form may, for example, take the form of a tablet in which the first and second compositions are arranged in two or more separated layers, preferably two layers.

  Alternatively, the first and second compositions may be multiparticulate.

  Multiparticulates include drug coatings or drug-containing non-pareil substrates, such as lactose spheres.

  Where the oral dosage form comprises multiparticulates, those of the first composition will generally be uncoated or have a non-functional coating, while those of the second composition are Usually it will have a functional coating such as an enteric coating. In such embodiments, the first composition may comprise beads containing or coated with both rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof, Alternatively, it may comprise a bead containing or coated with rosiglitazone or a pharmaceutically acceptable salt thereof and a mixture of beads containing or coated with donepezil and a pharmaceutically acceptable salt thereof. . The multiple particles of this embodiment may be filled in a capsule.

  When the immediate release composition is in tablet form, suitable diluents include saccharose, such as lactose and maltose. More suitably, the composition is primarily lactose, optionally supplemented with other formulation aids such as magnesium stearate.

  Alternatively, as described above, the immediate release composition is in the form of multiparticulates that are not coated for immediate action of rosiglitazone or a pharmaceutically acceptable salt and donepezil or a pharmaceutically acceptable salt thereof. There may be.

  Delayed release may conveniently comprise multiparticulates such as multiparticulate spheres obtained by use of gastroresistant formulations such as enteric formulations and coated with gastric resistant polymers. Suitable gastric resistant polymers are known in the art and are described, for example, in WO2005 / 013935. They include polymers such as methacrylic resin, cellulose acetate, carbomer, polyvinyl acetate phthalate and hydroxypropylmethylcellulose phthalate.

  Sustained release provides release of the active agent over a maximum of 26 hours, suitably 4-24 hours, more preferably 12-24 hours.

  Sustained release is typically provided by the use of a non-disintegrating or eroding matrix in the form of a sustained release matrix, usually a tablet.

  The sustained release matrix may be a tablet formulation. Suitable non-disintegrating matrix tablet formulations are known in the art and are provided, for example, as part of one or more methacrylate resins, cellulose acetate, carbomer and hydroxypropyl methylcellulose in the tablet.

  Alternatively, sustained release can be achieved by providing multiparticulates (described above) coated with a semipermeable membrane such as ethyl cellulose polymer.

The oral dosage form described above may be coated with an enteric membrane, and thus, in yet another aspect of the invention, an oral dosage form is provided comprising an erodible core and an erodible coating around the core, wherein the core Is
A first composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof formulated in an immediate action form through an aqueous medium; and formulated for sustained release through an aqueous medium; A second composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof.

  The erosive coating may extend substantially completely through the coating, but may further include one or more openings that do not penetrate the core and communicate from the environment of use to the core, wherein Release of rosiglitazone and donepezil from the core occurs substantially from the opening (s) and by erosion of the coating under certain pH conditions.

  The core may include a single layer of each of the first and second compositions.

  It is preferred that the erosion of the coating is pH dependent and either partially or totally decomposes, becomes permeable or can dissolve via the environmental fluid to bring the fluid into contact with the core. Preferably, the erodible coating is an enteric coating, i.e. it is dissolved and is preferably greater than pH 4.5, more preferably in the range of pH 4.5-8 and most preferably pH 5-7, Has a predetermined pH threshold.

  Suitable materials and mixtures thereof for use as pH-dependent erosion coating materials are known and described, for example, in WO 2005/013935. In particular, suitable enteric materials include methacrylic acid polymers and copolymers, such as those based on those sold under the trademark Eudragit L30.

A typical sized opening of the coating is also described in WO2005 / 013935. In general, they range from about 0.19 to about 50.3 mm ² and correspond to circular openings having a diameter in the range of 0.5 mm to 8 mm, preferably ² mm to 4 mm. The size of the opening (s) will depend on the overall size of the tablet and the desired release rate. The opening (s) may have any shape, but a circular shape, for example a substantially circular or elliptical shape, is generally preferred.

  The opening can be formed by the method described in WO 2005/013935, for example using a mechanical bit or laser beam or by punching a hole. Alternatively, the opening (s) may be formed in situ by forming a coating containing a pore-forming agent, ie, a substance that will dissolve in the stomach to create micropores in the coating. Can be formed.

  The opening (s) may comprise 0.25-70%, more typically 10-70% of the total surface area.

  The coating may be provided with one, two or more openings, and embodiments having two openings are particularly suitable when the core includes separate layers of the first and second compositions. . In this case, the core and coating may be arranged such that the first opening is accessible to the first composition and the second opening is accessible to the second composition.

  As protection against the core material, it may be preferable to provide a standard sealing coating on either the core or the dosage form after formation of the opening (s) to prevent contamination through the opening prior to administration. .

  The above dosage forms will be released in a manner that maintains the plasma concentrations of both drugs at the optimal concentration for 24 hours so that a once-daily dosage form combining rosiglitazone and donepezil is possible.

  As already mentioned above, the inventors have shown that rosiglitazone is most effective in the treatment of subjects who are not homozygous for APOE4, particularly subjects who do not carry the APOE4 allele.

  Accordingly, the above uses and methods for the combination of rosiglitazone and donepezil apply equally to the particular oral dosage form of this aspect of the invention.

  Although it is preferred that rosiglitazone and donepezil be co-formulated, it is alternatively preferred that they can be administered to the isolated composition simultaneously or sequentially. Typically, if rosiglitazone and donepezil are not administered simultaneously, they are administered within a period of time having a therapeutically effective plasma concentration for an overlapping period. Suitably, when rosiglitazone is administered in a composition not containing donepezil, it is formulated for once daily administration. If each active ingredient is to be administered once daily, each active ingredient will be sufficient to be taken daily.

  A suitable daily dose of rosiglitazone (eg as rosiglitazone maleate) will typically be in the range of 0.01 mg to 12 mg (eg 2 mg, 4 mg or 8 mg daily).

  A daily dose of 8 mg or more, for example 8 mg, may be particularly suitable. In the context of the present application relating to POE4 heterozygotes, administration of high doses of rosiglitazone (eg, 4 mg or more, eg, 4 mg or 8 mg) would appear to be effective.

  A suitable daily dose of donepezil (eg as donepezil hydrochloride) will typically be 2-5 mg, eg 5 mg or 10 mg.

  Thus, suitable dosage forms according to the present invention may contain 2 mg, 4 mg or 8 mg rosiglitazone (eg as rosiglitazone maleate) and 5 mg or 10 mg donepezil (eg as donepezil hydrochloride).

  It will be appreciated that the drug combinations of the present invention may find use in prophylaxis as well as in treatment of subjects suffering from (more suitably) mild cognitive impairment, Alzheimer's disease or other dementias.

  The invention will now be further described with reference to examples and figures:

  FIG. 1 shows the model-modified ADAS-cog change from the reference date in the comprehensive analysis population of Example 2.

  FIG. 2 shows the model modified ADAS-cog change from the baseline date in the genotype population of Example 2 by treatment plan and APOE allelic status.

  FIG. 3 shows a plot of model-modified ADAS-cog changes from baseline in APOE4 heterozygous (“Het”) and APOE4 homozygous (“Homo”) populations.

  Examples 1 and 2 relate to formulations containing rosiglitazone maleate and treatment with rosiglitazone is most effective in patients who do not have the APOE4 allele and is at least therapeutic in patients who are homozygous for APOE4 Prove that you have.

  Example 3 relates to a variety of formulations containing rosiglitazone in combination with donepezil.

  Example 1-Preparation of rosiglitazone maleate sustained release tablet

  Sustained release tablets containing 2 mg, 4 mg or 8 mg of the PPARγ agonist rosiglitazone (in the form of maleate) were prepared according to the method described in WO 05/013935 (corresponding to Example 3 herein) It was done.

(A) 2 mg rosiglitazone sustained release tablet The core is formed from the following composition by compression to form 200 mg of 7 mm normal concave bilayer tablet (50 mg immediate release layer and 150 mg modified release layer) It was.

  The tablet cores were coated with a HPMC protective coating and polymethacrylic acid resin soluble at a pH of 5.5 to a total weight of 217.3 mg.

  A 3.0 mm diameter opening was drilled in the coating on the first surface of each bilayer of the coated core to expose the surface of the core.

  The final tablet contained 0.75 mg rosiglitazone in the 2 mg rosiglitazone-immediate release layer and 1.25 mg rosiglitazone in the modified release layer.

(B) 4 mg rosiglitazone sustained release tablet A core was formed from the following composition by compression to form a 200 mg 7 mm normal concave bilayer tablet (50 mg immediate release layer and 150 mg modified release layer) .

  The tablet cores were coated with a HPMC protective coating and polymethacrylic acid resin soluble at a pH of 5.5 to a total weight of 217.3 mg.

  A 3.0 mm diameter opening was drilled in the coating on the first surface of each bilayer of the coated core to expose the surface of the core.

  The final tablet contained 1.5 mg rosiglitazone in the 4 mg rosiglitazone-immediate release layer and 2.5 mg rosiglitazone in the modified release layer.

(C) 8 mg rosiglitazone maleate sustained release tablet The core is compressed from the following composition to form 200 mg 7 mm normal concave bilayer tablet (50 mg immediate release layer and 150 mg modified release layer) Been formed.

  The tablet cores were coated with a HPMC protective coating and polymethacrylic acid resin soluble at a pH of 5.5 to a total weight of 217.3 mg.

  A 3.0 mm diameter opening was drilled in the coating on the first surface of each bilayer of the coated core to expose the surface of the core.

  The final tablet contained 3 mg rosiglitazone in the 8 mg rosiglitazone-immediate release layer and 5 mg rosiglitazone in the modified release layer.

Example 2-Effect of PPARγ agonist (rosiglitazone maleate) treatment on ADAS-cog and CIBIC + in Alzheimer's disease patients

Methods Analysis of the total inclusion analysis (ITT) population was performed on 511 subjects randomly assigned to one of the four treatment plans. Genotyping analysis was performed on 63% (323/511) of the ITT population.

  The patient population, including Caucasian males and females aged 50-85 who had been diagnosed with mild to moderate AD, had not received medications that could adversely affect the study (eg, PPARγ agonists or general AD Drug) or other potentially disadvantageous illness (eg diabetes or major mental illness).

  Patients received either placebo or one of three dose concentrations of sustained release rosiglitazone provided once daily (2 mg, 4 mg and 8 mg tablets as described in Example 1). Patients have a cognitive Alzheimer's disease rating scale (ADAS-cog; see Rosen WG et al. Am. J. Psychiatry. (CIBIC +; see Knopman DS et al. Neurology 1994 44: 2315-2321) for further information; and secondary assessments were made at study start date (baseline date) and study duration (treatment 8, 16, and 24 weeks later) Dementia Disability Assessment (DAD, see Gelinas L et al. Am J Occup Ther for more information. 1999 53: 471-81) and the neuropsychiatric evaluation test (NPI, see Cummings et al. (1994) Neurology 44, 2308-2314 for more information).

  APOE genotype was determined using the TaqMan PCR based method of McLeod et al. 2001 below.

  All statistics reflect the last observed assessment carried forward (LOCF) measurement to the missing data in the time series data.

Tables 8 and 9 summarize genotypes by treatment plan and age and gender details of all ITT populations.

Results It should be noted that in the case of ADAS-cog, higher scores show a reduced cognitive function. Therefore, a negative change from the reference date during the study period indicates an improvement, and a positive change from the reference date indicates a decrease. Similarly, a negative treatment difference indicates that treatment resulted in an improvement compared to placebo, and a positive treatment difference indicates that treatment resulted in a decrease compared to placebo.

  A higher CIBIC + score indicates a higher concentration drop with a score not exceeding 4 signifying clinical improvement and a score exceeding 4 signifying clinical decline. Thus, a negative CIBIC + treatment difference indicates that treatment resulted in an improvement compared to placebo, and a positive treatment difference indicates that treatment resulted in a decrease compared to placebo.

ITT Population Table 10 describes CIBIC + results after 24 weeks of testing of the model modified ADAS-cog change from the baseline date and each of the four treatment regimens of the ITT population. FIG. 1 shows the model-modified ADAS-cog change from the baseline date of the ITT population during the study period (analysis includes adjustment of baseline score, country, mini mental state test screening, and baseline body mass index effect) )

The ADAS-cog data in Table 10 and FIG. 1 support the trend of clinical improvement (ie, negative change from baseline) as a result of treatment with the PPARγ agonist rosiglitazone. At any point, there is a final improvement in the population that is analyzed as a whole. However, statistical analysis of the effects of rosiglitazone treatment in AD patients shows that this trend is not statistically significant. CIBIC + results did not produce a distinguishable difference between treatment group and placebo at 24 weeks.

Genotype populations (influencing the introduction of two additional subjects) Tables 11 and 11a show the results of APOE4 allele determination in genotype populations. Although the treatment regimen is assigned prior to APOE4 allele determination, some of the less common phenotypes show some groups (for example, the majority of APOE4 homozygotes are 8 mg rosiglitazone In general, there is a good distribution of phenotypes between the various groups as a result of statistical averaging.

  An analysis of ADAS-cog changes after a 24 week study by APOE allelic status and treatment plan is shown in Table 12 below.

  A prospective defined test of the interaction between APOE retention status and ADAS-cog total score change 24 weeks from baseline was significant (P = 0.194). It has been demonstrated that the improvement is due to treatment with the highest 8 mg rosiglitazone dose compared to placebo (P = 0.027), a general improvement in cognitive function as a result of treatment with the PPARγ agonist rosiglitazone Subsequent exploratory studies revealed that 24 weeks later, APOE4- (no APOE4 allele) patients showed a tendency.

  APOE4 heterozygotes (those with a single APOE4 allele) do not show a clear trend. Although decreased in the group receiving 2 mg rosiglitazone, both 4 mg and 8 mg dosages show little change and are not individually significant after 24 weeks of treatment.

APOE4 homozygotes (with two APOE4 alleles) show a relatively large positive change in ADAS-cog score as a result of rosiglitazone treatment. Although the sample number was small, there was some evidence that the decrease was due to treatment of all three dose concentrations after 24 weeks of treatment (unadjusted P <0.05). However, the extent of clinical decline as a result of treatment decreases with increasing dose concentration. It is not clear whether the clinical decline in the treatment group is due to rosiglitazone or due to the natural progression of Alzheimer's disease.

  FIG. 2 shows a plot of model modified ADAS-cog change from baseline in populations analyzed by treatment plan and APOE allelic status (carriers of one or two APOE4 alleles shown together) . FIG. 3 shows that data on APOE4 heterozygotes (indicated by “Het E4 +”) is separated from data on APOE4 homozygotes (indicated by “Homo E4 +”).

  A clear trend of cognitive improvement as a result of rosiglitazone treatment is particularly evident in APOE4- individuals. At any time (weeks 8, 16 and 24), the placebo group shows a continuous decline in cognitive function, while the groups treated with 2 mg, 4 mg or 8 mg PPARγ agonist show a marked improvement.

  The situation with APOE4 + individuals is less clear. After 8 weeks of treatment, the group receiving placebo shows a slight decrease in cognitive function, while all groups receiving rosiglitazone (2 mg, 4 mg or 8 mg) show a slight improvement. After 16 weeks of treatment, treatment with 4 mg and 8 mg shows the same or better clinical status, but the group receiving placebo shows a continuous decline in cognitive function. Treatment with 2 mg rosiglitazone shows a greater reduction than placebo. Finally, after 24 weeks of treatment, a large and surprising improvement in APOE4 carriers receiving placebo is observed. This apparent improvement can affect a small number of subjects with unexpected and significant improvements in ADAS-cog scores. All three rosiglitazone treatment groups have ended clinical decline, and as a result of the significant improvement of the placebo group at this point, rosiglitazone treatment appears to show a clinical decline compared to placebo. The clinical decline observed in some APOE4 + groups may be due to the natural clinical course of AD.

  FIG. 3 shows the APOE4 heterozygous results separated from the APOE4 homozygous results. Although the number of APOE4 homozygotes is small, all APOE4 homozygotes are treated with rosiglitazone that has experienced clinical decline, whereas APOE4 heterozygotes administered high doses of rosiglitazone (4,8 mg) It can be seen that the study period remains largely baseline.

  Similar results were demonstrated using the Dementia Disability Assessment (DAD) test (Gelinas L et al. Am J Occup The 1999 53: 471-81). A predictively defined study of the interaction between APOE4 carrier status at 24 weeks and the DAD score was significant (P = 0.006). The next test qualitatively demonstrated a pattern of results similar to ADAS-Cog: the APOE4- subject demonstrated improvement on DAD, while the APOE4 + subject did not demonstrate improvement.

  Similar results were shown using the Neuropsychiatric Symptom Assessment (NPI) test (Cummings et al. (1994) Neurology 44, 2308-2314). A predictively defined study of the interaction between APOE4 carrier status and NPI score at 24 weeks was significant (P = 0.086). The following test qualitatively demonstrated a pattern of results similar to ADAS-Cog: the APOE4- subject demonstrated improvement over NPI, while the APOE4 + subject did not demonstrate improvement.

  Table 13 and Table 13a (which is the latest analysis taking into account additional subjects) show CIBIC + results after 24 weeks, separated by APOE4 allele status and treatment regimen. Since there was no evidence of interaction between treatment and APOE4 copies, the following differences between subgroups are likely due to stochastic errors rather than differential effects.

  All APOE4- (without the APOE4 allele) patients show a slight improvement over 24 weeks with the greatest improvement observed in the group treated with 2 mg rosiglitazone (unadjusted P = 0.052) ).

  APOE4 heterozygotes (those with a single APOE4 allele) show a reduction in the group treated with 2 mg rosiglitazone (P = 0.056). There is a smaller decrease in the group receiving 4 mg rosiglitazone (although the comparison does not approach the significance of the preliminary analysis) and a slight improvement is seen in the group receiving 8 mg rosiglitazone.

Although the extent of improvement decreased with the therapeutic dose, all APOE4 homozygotes (those with the APOE4 allele) show a slight improvement in CIBIC + therapeutically over 24 weeks compared to placebo.

Discussion The results of Example 2 show that treatment of AD patients with PPARγ for rosiglitazone leads to a non-statistically significant trend towards overall improvement of the ITT population as a whole.

  In the tested population, there was a basis for cognitive impairment (as measured by ADAS-cog) in patients who did not have the APOE4 allele on 8 mg rosiglitazone. The mean change from placebo at 24 weeks for patients without the APOE4 allele on 8 mg rosiglitazone was -2.86, P = 0.027.

  There was no basis for improved therapeutic cognition (as measured by ADAS-cog) in patients carrying the APOE4 allele in the population tested. However, the separation of patients with 2 copies of the APOE4 allele and those with 1 copy is not accompanied by a significant trend (eg, possible stabilization of cognitive function) in patients with 1 copy of the APOE4 allele. This suggests the greatest cognitive decline (as measured by ADAS-cog) in patients carrying 2 copies of the APOE4 allele (but may be due to the natural progression of the disease rather than a response to rosiglitazone).

Example 3-Oral dosage form containing rosiglitazone (eg as maleate) and donepezil (eg as hydrochloride)
Formula A
Formulation A has a bilayer tablet core comprising an immediate release layer and a modified release layer as shown in Table 14. The tablets were then coated and pierced to form DiffCORE tablets (in a manner similar to that described in WO2005 / 013935).

  The tablet cores were coated with a HPMC protective coating and polymethacrylic acid resin soluble at pH 5.5.

  A 3.0 mm diameter opening was drilled in the coating on the first surface of each bilayer of the coated core to expose the surface of the core.

  The final tablet is 2 mg, 4 mg or 8 mg rosiglitazone (0.75 mg, 1.5 mg or 3 mg rosiglitazone in the immediate release layer and modified release, respectively, with either 5 mg or 10 mg donepezil in the immediate release layer 1.25 mg, 2.5 mg or 5 mg rosiglitazone in the layer).

Formula B
Formula B is an enteric matrix controlled bilayer tablet.

  In Table 15 below, donepezil is part of the immediate release layer of the tablet for a range of possible strength combinations:

  The final tablet is 2 mg, 4 mg or 8 mg rosiglitazone (0.75 mg, 1.5 mg or 3 mg rosiglitazone in the immediate release layer and modified release, respectively, with either 5 mg or 10 mg donepezil in the immediate release layer 1.25 mg, 2.5 mg or 5 mg rosiglitazone in the layer).

Formula C
Formula C includes drug-coated pellets filled into capsules. Capsules are filled with a mixture consisting of immediate release rosiglitazone, immediate release donepezil and enteric coated rosiglitazone pellets. The pellet formulation is shown in Table 16:

  Rosiglitazone and donepezil immediate-acting pellets were coated with an HPMC protective coating. A portion of the protective coating pellet was enteric coated with a polymethacrylic acid resin soluble at pH 5.5.

  Final capsules are either 2 mg, 4 mg or 8 mg rosiglitazone (either 0.75 mg, 1.5 mg or 3 mg rosiglitazone in immediate release pellets and modified release pellets with either 5 mg or 10 mg donepezil in immediate release pellets, respectively. 1.25 mg, 2.5 mg or 5 mg rosiglitazone).

All publications mentioned in this application, including patents and patent applications, are hereby incorporated by reference wherever possible.
In the description and in the claims, unless the context requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” are defined integers, steps, groups of integers. It will also be understood to include the meaning of including a group of steps but not excluding other integers, steps, groups of integers or groups of steps.

The model correction ADAS-cog change from the reference | standard day in the comprehensive analysis population of Example 2 is shown. FIG. 5 shows model-modified ADAS-cog changes from baseline in the genotype population of Example 2 by treatment plan and APOE allelic status. FIG. 5 shows a plot of model-modified ADAS-cog change from baseline in APOE4 heterozygous (“Het”) and APOE4 homozygous (“Homo”) populations.

Claims (47)

  A composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.   Rosiglitazone or its pharmaceutically acceptable salt and donepezil or its pharmaceutically acceptable for use in improving cognitive function in subjects suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia A composition comprising a salt together with a pharmaceutically acceptable diluent or carrier.   A method for improving cognitive function in a subject suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia, comprising a safe and effective amount of rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil Or a method comprising administering to a subject a pharmaceutically acceptable salt thereof.   Rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable thereof in the preparation of a medicament for improving cognitive function in a subject suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia Use of a composition comprising a prepared salt.   Rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutical thereof for simultaneous, separate or sequential use to improve cognitive function suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia An acceptable salt combination.   6. The composition of claim 2, the method of claim 3, the use of claim 4, or the combination of claim 5, wherein the subject is not homozygous for the APOE4 allele.   6. The composition of claim 2, the method of claim 3, the use of claim 4, or the combination of claim 5, wherein the subject does not carry the APOE4 allele. A method for improving cognitive function in a subject suffering from or susceptible to MCI, Alzheimer's disease or other dementia, wherein the subject is not homozygous for the APOE4 allele, comprising:
i) screening the subject to determine that the subject is not homozygous for the APOE4 allele;
ii) administering to the subject a composition comprising a safe and effective amount of rosiglitazone or a salt thereof and donepezil or a pharmaceutically acceptable salt thereof.   9. The method of claim 8, wherein the screening step (i) involves determining that the subject carries a single sequence APOE4 allele.   9. The method of claim 8, wherein the screening step (i) involves determining that the subject is APOE4.   11. A method according to any one of claims 8 to 10, wherein the subject is suffering from or susceptible to MCI (especially amnestic MCI).   11. The method of any one of claims 8-10, wherein the subject is suffering from or susceptible to Alzheimer's disease.   Is suffering from MCI, Alzheimer's disease or other dementia as an aid in predicting a subject's responsiveness to administration of a composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof Or a method of screening for susceptible subjects, comprising screening to determine whether the subject carries 0 or 1 copy of the APOE4 allele.   14. The method of claim 13, including a test to determine whether the subject is APOE4.   (I) a composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof, and (ii) a PPARγ agonist (usually a pharmaceutical composition) to a subject that is not homozygous for the APOE4 allele A kit containing instructions to administer administration (in the form of a product).   16. The composition, method, use, combination, kit of any one of claims 1-15, wherein rosiglitazone is in the form of rosiglitazone maleate.   16. A composition, method, use, combination or kit according to any one of claims 1 to 15, wherein donepezil is in the form of donepezil hydrochloride.   Oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation (including various metered-pressure pressurized aerosols, fine dust or mist generated by nebulizers or inhalers), transdermal (skin 18. A composition according to any one of claims 1, 2, 16 or 17 which is formulated for administration (including via a medical patch). First composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof and a donepezil or a pharmaceutically acceptable salt thereof formulated in an immediate action form through an aqueous medium. Formulated in a modified release form through an aqueous medium An oral dosage form comprising a second composition comprising rosiglitazone or a pharmaceutically acceptable salt thereof.   20. The oral dosage form of claim 19, wherein the first and second compositions are multiparticulates.   21. The oral dosage form of claim 20, wherein the multiparticulates are drug-containing lactose spheres.   The oral dosage form of claim 20 or claim 21, wherein the multiparticulates comprising the first composition are coated and the multiparticulates comprising the second composition have an enteric membrane.   The oral dosage form according to any one of claims 20 to 22, wherein the multiparticulates are filled in a capsule.   20. The oral dosage form of claim 19, wherein the first and second compositions require a tablet form arranged in two or more independent layers.   25. The oral dosage form of claim 24, wherein the first and second compositions are arranged in two separate layers.   25. The oral dosage form of claim 24, wherein the immediate release composition comprises sucrose.   29. The oral dosage form of claim 28, wherein the immediate release composition comprises lactose and may comprise magnesium stearate.   28. The oral dosage form according to any one of claims 19 to 27, wherein the modified release comprises delayed release and / or sustained release.   28. The oral dosage form of any one of claims 24-27, wherein the second composition comprises a sustained release composition in a tablet formulation.   24. The oral dosage form according to any one of claims 20 to 23, wherein the second composition comprises a sustained release composition in the form of multiparticulates coated with a semipermeable membrane.   31. An oral dosage form according to any one of claims 19 to 30, which is coated with an enteric membrane.   31. An erodible core comprising an oral dosage formulation according to any one of claims 19-30 and an erodible coating around the core, wherein the erodible coating extends substantially completely through the coating. One or more openings that do not penetrate into the core and communicate from the environment of use to the core, wherein the release of rosiglitazone or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof from the core, An oral dosage formulation that occurs through the opening (s) and coating erosion under substantially predetermined pH conditions.   33. The oral dosage formulation of claim 32, wherein the coating erosion is pH dependent.   34. The oral dosage form of claim 33, wherein the erodible coating is an enteric coating. The opening of the film is in the range of about 0.19～ about 50.3 mm ^2, corresponding to the circular opening having a diameter in the range of 0.5Mm～8mm, according to any one of claims 32 to 34 Oral dosage form.   The core includes individual layers of the first and second compositions, and the coating allows the first opening to access the first composition and the second opening to access the second composition. 36. An oral dosage form according to any one of claims 32 to 35, having two openings arranged in such a manner.   37. An oral dosage form according to any one of claims 19 to 36 for use in improving cognitive function in a subject suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia.   37. A method for improving cognitive function in a subject suffering from or susceptible to mild cognitive impairment, Alzheimer's disease or other dementia, comprising: targeting an oral dosage form according to any one of claims 19-36 A method comprising administering.   40. The method of claim 38, wherein the subject is not homozygous for the APOE4 allele.   40. The method of claim 38, wherein the subject does not carry the APOE4 allele. A method for improving cognitive function in a subject suffering from or susceptible to MCI, Alzheimer's disease or other dementia, wherein the subject is not homozygous for the APOE4 allele, comprising:
i) screening the subject to determine that the subject is not homozygous for the APOE4 allele;
ii) A method comprising administering to the subject an oral dosage form according to any one of claims 19-36.   42. The method of claim 41, wherein screening step (i) involves determining that the subject carries a single copy of the APOE4 allele.   42. The method of claim 41, wherein the screening step (i) involves determining that the subject is APOE4.   44. The method of any one of claims 38-43, wherein the subject is suffering from or susceptible to MCI (particularly amnestic MCI).   44. The method of any one of claims 38 to 43, wherein the subject is suffering from or susceptible to Alzheimer's disease.   37. An oral dosage form according to any one of claims 19 to 36, wherein the rosiglitazone is in the form of rosiglitazone maleate.   37. The oral dosage form according to any one of claims 19 to 36, wherein donepezil is in the form of donepezil hydrochloride.

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